Introduction
Drug delivery to the central nervous system (CNS) remains a major hurdle due to the restrictive nature of the blood-brain barrier (BBB). Traditional systemic administration often results in poor drug penetration into the brain, necessitating alternative strategies. Intranasal drug delivery has gained attention as a direct route to the brain, bypassing the BBB through the olfactory and trigeminal pathways.
Nasal in situ gels are liquid at room temperature but transform into a gel upon contact with the nasal mucosa due to changes in temperature, pH, or ionic strength. This transformation increases the retention time of the drug and enhances bioavailability. In situ gels offer several advantages including ease of administration, non-invasiveness, and rapid onset of action—features crucial for CNS-acting drugs such as anti-epileptics, anti-depressants, and anti-Parkinson agents.
2. Materials and Methods
2.1 Polymers and Excipients Used
Commonly used polymers include:
- Poloxamer 407 and 188: Thermosensitive behavior, providing gelation at nasal cavity temperature.
- Carbopol 934P: pH-sensitive mucoadhesive polymer.
- HPMC and MC: Provide viscosity and support sustained drug release.
- Chitosan: Enhances mucoadhesion and has permeation-enhancing properties.
| Polymer | Type | Function | Concentration Range |
|---|---|---|---|
| Poloxamer 407 | Thermosensitive | Gelation | 15–22% w/v |
| Carbopol 934P | pH-sensitive | Mucoadhesion | 0.2–0.5% w/v |
| HPMC (K100M) | Viscosity enhancer | Sustained release | 0.5–2% w/v |
| Chitosan | Mucoadhesive | Enhances absorption | 0.25–1% w/v |
2.2 Drug Incorporation
CNS-acting drugs like midazolam, zolmitriptan, or levodopa are dissolved or dispersed in polymeric solutions. The solution is sterilized using membrane filtration and packed in pre-sterilized containers.
2.3 Evaluation Parameters
- Viscosity: Measured using Brookfield viscometer.
- Gelation Temperature: Determined using a water bath method.
- Mucoadhesive Strength: Tested using a texture analyzer.
- Drug Content: Evaluated by UV or HPLC analysis.
- In Vitro Drug Release: Conducted using Franz diffusion cells.
3. Results and Discussion
Several studies have shown that nasal in situ gel formulations provide:
- Improved drug retention in the nasal cavity.
- Controlled and sustained drug release profiles.
- Higher CNS bioavailability compared to oral or IV routes.
3.1 Sample Data Table
| Formulation | Gelation Temp (°C) | Mucoadhesion (dyn/cm²) | % Drug Release (6 h) | Nasal pH Tolerance |
|---|---|---|---|---|
| F1 (Poloxamer 407 + Carbopol) | 34.2 | 58 | 78.5% | Acceptable |
| F2 (Poloxamer 407 + HPMC) | 33.5 | 42 | 71.2% | Acceptable |
| F3 (Poloxamer 407 + Chitosan) | 34.8 | 63 | 83.1% | Acceptable |
The presence of chitosan significantly enhanced mucoadhesion and drug release. Formulations remained liquid at room temperature and gelled upon exposure to nasal temperature (32–35°C). These gels were found to be non-irritant and suitable for nasal mucosa.
4. Conclusion
Nasal in situ gel systems are a promising approach for CNS drug delivery due to their ability to bypass the BBB, prolong nasal residence time, and offer sustained drug release. Polymers such as Poloxamer, Carbopol, and Chitosan play a pivotal role in optimizing the formulation. Despite challenges such as limited drug load and nasal enzymatic degradation, these systems show great potential in improving therapeutic outcomes for neurological disorders. Further research into patient-centered designs and clinical trials will be crucial for translation into commercial applications.
References
- Illum L. “Transport of drugs from the nasal cavity to the central nervous system.” Eur J Pharm Sci. 2000;11(1):1–18.
- Ugwoke MI, et al. “Nasal drug delivery to the brain: review of the literature.” Drug Delivery. 2001;8(2):105–112.
- Kumar M, Misra A, Mishra AK. “Nose-to-brain drug delivery: an overview of in situ gel-based systems.” Drug Deliv. 2019;26(1):252–269.
- Mahajan HS, Gattani SG. “Nasal in-situ gel of loratadine: formulation and evaluation.” J Pharm Sci. 2010;99(2):627–632.
- Vyas TK, et al. “Intranasal drug delivery for brain targeting.” Curr Drug Deliv. 2005;2(2):165–175.
- Casettari L, Illum L. “Chitosan in nasal delivery systems for therapeutic drugs.” J Control Release. 2014;190:189–200.
- Pardeshi CV, Belgamwar VS. “Direct nose to brain drug delivery via integrated nanocarrier systems.” Drug Discov Today. 2013;18(1–2):96–107.
- Sharma A, et al. “Mucoadhesive in situ nasal gel of zolmitriptan for the treatment of migraine.” Int J Pharm Pharm Sci. 2014;6(2):320–324.
- Shinde UA, et al. “Formulation development and evaluation of intranasal in situ gel of midazolam.” J Pharm Sci Res. 2019;11(5):1834–1838.
- Baranowski P, et al. “Challenges in intranasal delivery of CNS-active drugs.” Expert Opin Drug Deliv. 2018;15(6):561–574.